Process for the preparation of piperazine derivatives



United States Patent Ofiice 2,859,216 Patented Nov. 4, 1958 PROCESS FORTHE PREPARATION OF PIPERAZINE DERIVATIVES No Drawing. Application June26, 1956 Serial No. 593,826

6 Claims. (Cl. 260268) This invention relates to new dinitriles carryingtwo tertiary amino groups and methods of providing them. Morespecifically it relates to N,N'-bis-(omega-cyano-nalkyl)-piperazines inwhich the cyanoalkyl group con tains more than three carbon atoms. Stillmore specifically it relates to N,N'-bis-(4-cyano-n-butyl)-piperazine.The nitriles of this invention are unique in that on hydrogenation theygive diamines of sufiicient stability for use in the preparation of highmolecular weight, fiber-forming polycarbonamides which are sensitive toacid dyes.

Heretofore, N,N' bis (omega cyano n alkyl)- piperazines in which thecyanoalkyl groups contain more than three carbon atoms have not beenknown. Van Dorp (Rec. trav. chim., 28, 81-5 (1909)) describes thepreparation of N,N'-bis-(cyanomethyl)-piperazine by reaction ofpiperazine with hydrogen cyanide and formaldehyde. Rob and Wolff (GermanPatent 641,597 (1937)) disclose the synthesis ofN,N'-bis-(2-cyanoethyl)-piperazine from acrylonitrile and piperazine.

The object of this invention is provision of N,N'-bis-(omega-cyano-n-alkyl)-piperazines which carry two tertiary nitrogenatoms and in which the cyanoalkyl groups contain more than 3 carbonatoms. More specifically its object is N,N'-bis-(4-cyano-n-butyl)-piperazines.

It is another object of this invention to provide a novel process forthe preparation of the said cyanoalkyl piperazines in good yield.

It is a further object of this invention to provide N,N-bis-(cyano-n-alkyl)-piperazines which canbe hydrogenated to giveN,N'-bis-(aminoalkyl)-piperazines of sulficient stability for use in thepreparation of deeply dyeable, fiber-forming polycarbonamides.

Still further objects of the invention will appear hereinafter.

The objects of this invention are achieved by heating at least twomolecular proportions of the omega-halogenonitrile of a normal fattyacid containing 4 or more carbon atoms with one molecular proportion ofpiperazine or a C-alkylated piperazine in the presence of two or moreequivalents of an aqueous alkali, separating the resultantbis-(cyanolkyl)-piperazine and freeing it of impurities which interferewith its catalytic hydrogenation to the corresponding diamine.

The preparation of mono-nitriles containing the 4- cyano-n-butyl group,such as 4-cyanobutyl-aminobutane, CNC H NHC H have been previouslydescribed by Gassenmeier and Hrubesch (German Patent 875,523 (1949)).This process is carried out by heating S-chlorovaleronitrile with excessprimary or secondary amine under pressure and liberating the aminehydrochloride obtained as a primary product by treatment with a strongalkali. Methods for the production of dinitriles by heat ing piperazinederivatives with halogenonitriles are not described.

The preferred dinitriles of this invention are those in which thecyanoalkyl groups contain 4 to 8 carbon atoms.

These are preferably produced by reactions involvingomega-chloronitriles of normal fatty acids containing 4 to 8 carbonatoms, viz. 4-chloro-n-butylronitrile, 5- chlorovaleronitrile,6-chlorocaponitrile and 7-chloroenanthonitrile. The preferredpiperazines are unsubstituted piperazine or C-alkylated piperazinescarrying up to two alkyl groups containing up to two carbon atoms pergroup. Of special interest because of its availability is 2,5-dimethylpiperazine.

Suitable alkalis for use in the process of this invention include thealkali metal carbonates, alkali metal hydroxides and alkaline earthhydroxides. Sodium carbonate is preferred because of its low cost andavailability.

The reaction is carried out by refluxing the reaction mixture of thepiperazine, chloronitrile, sodium carbonate and water for about two toten hours. The temperature of the refluxing mixture is in the range -125C.'

Higher temperatures could be employed, if desired, to accelerate thereaction but this would necessitate use of an autoclave in which thereaction could be carried out under pressure. At least two molecularproportions of chloronitrile are required for each mole of piperazinebut to obtain the best yields an excess of 5 to 10% of the theoreticalamount-of chloronitrile should be employed. One equivalent of sodiumcarbonate or a slight excess thereof should be employed for eachmolecular proportion of chloronitrile. Preferably sufiicient water isused to give a sodium carbonate solution having a concentration ofaround 30%. A small amount of potassium iodide may be added as areaction catalyst but this is not essential and good results areobtained in its absence. If desired the-chloronitrile may be addedgradually to the refluxing mixture of the other agents. Good mechanicalagitation is desirable to facilitate reaction.

When the reaction is complete, the product may be isolated by variousmethods involving decantation of phases, crystallization, solventextraction, distillation, etc. In order to obtain a productsuitable forutilization as an intermediate for the preparation of diamines, it mustbe substantially free of unreacted chlorovaleronitrile or otherproducts, which act as catalyst poisons, or otherwise interfere with thecatalytic hydrogenation process. It has been discovered that this can bedone by steaming the crude product, crystallizing the nitrile hydrateand subsequently blowing with preheated nitrogen gas. This treatmentremoves organic impurities and water to give anhydrous dinitrile whichcan be employed directly in the hydrogenation process.

The N,N-bis-(4-cyano-n-butyl)-piperazine or" this invention is asubstantially colorless, crystalline product which melts atapproximately 25 C. when pure and boils at 180-4 C. at 0.1 to 0.3 mm.pressure. It readily absorbs Water forming a crystalline monohydrateWhose melting point is approximately 70 C. The nitrile titrates as aweak monoacid base. The solubility of the hydrate in water is 4.5% at 4C., 7% at 30 C. and at temperatures approaching the boiling point ofwater, it dissolves readily in an equal weight of water. 011hydrogenation with Raney cobalt, it gives the diamine, N,N-'oi s- 5aminop entyl) -piperazine.

N,N'-bis- (4-cyanobutyl)-2,5-dimethyl piperazine is a substantiallycolorless solid melting at approximately 67 C. and boiling at -180 C.under a pressure of 0.1 to 0.3 mm. It does not form a stable hydratewith water as is the case with the unsubstituted cyanobutyl piperazinedescribed above. On hydrogenation, it gives the diamine,

' N,N'-bis- (S-aminop entyl) -piperazine.

The invention may be better understood in greater detail from thefollowing examples describing the preparation ofN,N'-bis-(4-cyano-n-butyl)-piperazines.. These examples are given forillustrative purposes only and are not intended to limit the invention.

Example 1 A charge of 44.6 g. piperazine having a purity of 96.5% (0.50mole), 58.3 g. anhydrous sodium carbonate (0.55 molel 'and 160ml.'water:was placed in'a 1-liteu3-necked flask-equipped with a refluxcondenser, an 'efiicient'stirrer I and a graduated dropping funnel; Thecharge was th'en' heated to. reflux with constant-agitation :and 136g."of'5- chlorovaleronitrile having a purity of 95% (1.1. moles) addedgradually at an approximately. constant rate over .a: period of minutes.Refluxing andstirring'were then continued for an additional 4.5 hours.The reaction mixture: atthis state consisted-of two liquid phases.-

The liquidphases. were decantedwithout cooling and the upper organiclayer mixed with an equal weight of. water, heated to dissolve andcooled in an ice bathto f crystallize the product which separated as themonohydrate. -When crystallization appeared to be complete after aboutone hour, the crystalswere filtered, washed with ml'.- water-andair-dried to constant weight. The L mother-liquor was then evaporated toabout 25% of its original volume'and filtered to recover a second cropof crystals. The mother liquor from-thelatter crystals was evaporated toconstant weight in a steam bath under. partial vacuum. The residue (6.5g.) was dissolved .in an equal weight of hot water and a third crop ofcrystals recovered. The total product weighed 124.3 g. This amounts to ayield of the monohydrate of N,N-bis-(4- cyanobutyl)-piperazineequivalent to 93.7% of the theoretical basedonpiperazine or 85.2% on achloro-. 30 valeronitrile basis. Thecrude monohydrate melted in therange 60 to 69 C.

Example 2 Eighty-nine pounds of piperazine (96.5%), one hundredseventeen pounds sodium carbonate and 30 gals. Wash liquid 'fromaprevious preparation of N,N-bis-(4- cyanobutyl)'-piperazine were placedin a steel reactor equipped with agitation, means for heating, arefluxcondenser and essential piping for filling and draining. Thesolution was heated to boiling and two hundred thirty pounds 95%5-chlorovaleronitrile pumped in over a period of approximately 30minutes. The mixture was then refluxed for two hours and decanted hotdiscarding the dense brine layer. The-crude product layer was pumped toa crystallization vessel and mixed with an equal Weight of water. Thismixture was heated to boiling and partially distilled to remove a smallamount of water, unreacted chloroval'eronitrile and other impurities.After this, the mixture was cooled, filtered and the crude crystalswashed'with water. ,The filtrate was discarded butthe washings wereretained for use as the solvent for subsequent batches of piperazine andsodium carbonate. The crystals were then melted and "run into a packedtower, in which the melt was subjected to countercurrent scrubbing withhot dry nitrogen to'remove water and traces of volatile impurities. Thedehydrated N,N'-bis- (4-cyanobutyl)-piperazine melts at approximately 25C. and is free of impurities which interfere with catalytichydrogenationwith Raney cobalt to the corresponding diamine,N,N-bis-(5-aminopentyl) -piperazine.

Example 3 A reactor was charged with 171 parts of 2,5-dimethylpiperazine, 432 parts'of chlorovaleronitrile, 31 8 'parts of sodiumcarbonate, 1000 parts of water and 2 parts of-' '-65 potassium iodide ascatalyst. The mixture was heated at: reflux for'itwo hours. Aftercooling to room: temperature,.-the. mixture :was. extracted-with benzeneand ithe' benzene; extract. distilled under reduced pressure to isolate:I. the product. An approximately 90% yield: of N,N:'-bis+ 70(4-cyanobutyl)=2,5 dimethy1- piperazine. wasobtained. Theproduct-distilledat' to C.- at apressure'of. 0.1. to 0.1mm. andmelted at66 to 67 C. V 1

The, N,N."-bi-s-(omega-cyano-nwalkyl) -piperazines of this invention inwhich the 'cyanoalkyl group contains 4 to 75 to give a crystalline salt.

8 carbon atoms are of outstanding value as intermediates This utilitymaybe demonstratedbyihydrbgenating the dinitriles in the presence of anactive cobalt catalyst, such as.Raney cobalt. Theresultantdiainineisreactedi iith an equimolar proportion of adipic acidiir' alcoholsolution A 50% aqueoussolution "of 47.5 parts of the abovesalt is placedina r evaporator with 4000 parts of a 50% aqueous-solutionofhexamethyl enediammonium adipate and 22 parts of acetic acid. Themixture is evaporated to-a -totaksolids'content of 75% and then, whilehot, charged into a nitrogen-purged autoclave. During the first halfhour of .the polymerization cycle, the system is closed while thetemperatureis to 200 C. A pressure of 250 pounds per square inchis;

maintained for an additional five hours while the tempera-v ture isslowly increased to 280"C. Pressure is then re duced to atmospheric overa l /z' hour period, the-te perature beingpe'rmitted to rise to 285 C.After. ma n-,-

taining this temperature for about 2'hours, the. polymeriza tio'nproduct is extruded as a'i'ibbon, quenched 5.0 grams per denier'anda 25%elongation;

Knit tubing prepared from the" aboveyarn isdyed by immersion forone-hour at theboil in ianaqueous' bath" containing the following:

2.0% AnthraquinoneGreen (CJ. 1078) 2.0% Sodium lauryl sulfate 10.0%Ammonium sulfate.

The bath to 'fabric'. ratio. is .ma-intained at.50;,l (bathzfabric). Thefabric is then scoured in Water oo taining 2.0% sodium lauryl sulfatefor 15 .minutes at 75 C., rinsed" and dried." It is observed to .have-.b,een.-z

dyed-a dark 'green..

When a similar tubing'of.polyhexamethyleneadipamide; yarn is' subjectedto the sam'eadyeing technique. as

scribed above, it acquires only a light'ishade ofgreen.

Diamines prepared from N,N-bis-(omega-cyano-n..

alkyl)-piperazines in which the. cyanoalkyl .groups contain less thanfour carbon atoms are too .unstab lei or use in the preparation ofmodified 'polycarbonamidesaa described above. "When N,N" bis (2 4aminopropylipip'erazine, prepared'by hydrogenation of N,N-'bis'- (2-- 1cyanoethYD-piperazine, was employed in the modified T polycarbonamidepreparation described above' it"was.

found to be of insuflicient stability for preparation ofa satisfactorypolymer. Decomposition was indicated .by," the low viscosity of themodified polymer and thefact that it contained an abnormallyhigh contentof ,titrat- Q able amine.

Diamines prepared by hydrogenation of 'N,"N-bis:f(,4- cyanobutyl)"alkyla'mines are also too unstable for use: in the preparation ofmodifiedpolycarbonamides of'the... type described.fExperimentsdemonstrated that over.

50% of N,N-bi's-'(5-aminopentyl')-n-butylamine was de.

composed when employed in place of'the N,N bis-(5A. polycarbonamideprep-i."

aminopentyll-piperazine in the aration previously described.

Having described my invention in detail, I claim: I I 1. 'A process forthe-preparation of .N,N'-'bis-(omega cyano-n-alkyl)-piperazines-. inwhich. the omega-want}; n-alkyl groups contain} to 8' carbon atoms byreaction g,

of a piperazine, selected from the group consisting of piperazine andC-alkyl substituted piperazines carrying 1 to 2 alkyl groups containing1 to 2 carbon atoms, with, at least, two molecular proportions of anomegahalogenonitrile of a normal fatty acid containing 4 to 8 carbonatoms in the presence of water and approximately one equivalent of analkali for each molecular proportion of the halogenonitrile, said alkalibeing selected from the group consisting of alkali metal hydroxides,alkali metal carbonates and alkaline earth hydroxides.

2. The process of claim 1 in which the piperazine is unsubstitutedpiperazine, the omega-halogenonitrile is 5- chloro-n-valeronitrile andthe alkali is sodium carbonate.

3. The process of claim 2 in which the piperazine is 2,5-dimethy1piperazine.

4. A process for the preparation of N,N'-bis-(4-cyanon-butyD-piperazineby the reaction of one molecular proportion of piperazine with 2.1 to2.2 molecular proportions of 5-chloro-n-valeronitrile and an aqueoussolution containing approximately one equivalent of sodium carbonate foreach molecular proportion of said chloronitrile and having aconcentration of around 30%, aforesaid reaction being carried out in thetemperature range of about 100-125 C.

5. The process of claim 4 in which the N,N-bis-(4-cyano-n-butyl)-piperazine is separated from the reaction mixture bydecanting the upper product phase from the hot mixture, crystallizing asthe monohydrate from a hot solution of this phase in an equal weight ofwater after steaming to remove volatile impurities, and subjecting themolten crystals of the hydrated product to a current of preheatednitrogen gas to remove water and any remaining impurities, saidseparated product being of satisfactory purity for catalytichydrogenation.

6. A process for the preparation of N,N'-bis- (4- cyano-n-butyl)-2,5-dimethyl-piperazine by the reaction of one molecular proportion of2,5-dimethyl-piperazine with 2.1 to 2.2 molecular proportions ofS-chloro-nvaleronitrile and an aqueous solution containing approximatelyone equivalent of sodium carbonate for each molecular proportion of saidchloronitrile and having a concentration of around 30%, aforesaidreaction being carried out in the temperature range of about 100-125" C.

References Cited in the file of this patent UNITED STATES PATENTS2,277,158 Sexton et a1. Mar. 24, 1942 FOREIGN PATENTS 641,597 GermanyFeb. 11, 1937 690,466 Great Britain Sept. 26, 1951

1. A PROCESS FOR THE PREPARATION OFN,N''-BIS(OMEGACYANO-N-ALKYL)-PIPERAZINES IN WHICH THEOMEGA-CYANON-ALKYL GROUPS CONTAIN 4 TO 8 CARBON ATOMS BY REACTION OF APIPERAZINE, SELECTED FROM THE GROUP CONSISTING OF PIPERAZINE, ANDC-ALKYL SUBSTITUTED PIPERAZINES CARRYING 1 TO 2 ALKYL GROUPS CONTAINING1 TO 2 CARBON ATOMS, WITH, AT LEAST, TWO MOLECULAR PROPORTIONS OF ANOMEGAHALOGENONITRILE OF A NORMAL FATTY ACID COPNTAINING 4 TO 8 CARBONATOMS IN THE PRESENCE OF WATER AND APPROXIMATELY ONE EQUIVALENT OF ANALKALI FOR EACH MOLECULAR PROPORTION OF HTE HALOGENONITRILE, SAID ALKALIBEING SELECTED FROPM THE GROUP CONSISTING OF ALKALI METAL HYDROXIDES,AND ALKALI METAL CARBONATES AND ALKALINE EARTH HYDROXIDES.